The skin, also known as the integumentary system, is the largest organ in the body. The skin is an organ with its own anatomy, physiology, and functions. For example, some of the integumentary system's functions are as a protection from the environment and microorganisms, as a sensory system, as a temperature control system, as an excretory system, and even as a chemical factory in the production of vitamin D. Unfortunately, as with any organ that has its own anatomy and physiology, comes pathology.
There are over 2000 disorders that can affect the integumentary system. Fitzpatrick, Polono, Suurmound, Color Atlas and Synopsis of Clinical Dermatology (1983). What separates the disorders of the integumentary system from other organs is that the symptoms of the disorders of the integumentary system are so readily sensed and palpable to the one afflicted and visible to that person and others. Additionally, the manifestations and symptoms of skin disorders are easily and immediately exacerbated by the sufferer of the disorder. For example, many of the 2000 disorders of the skin manifest with lesions that carry with them the symptoms of pruritis (“itching”), erythema (heat and redness), and algesia (pain). A person trying to relieve the symptom of a skin disorder may make the condition worse by consciously or, even more commonly, unconsciously scratching at lesions manifested by the disorder. These differences, as well as many others, make the treatment of skin ailments a unique and difficult problem.
Some of the more common and well-recognized diseases are the psoriatic disorders and the specific abnormalities that fall within the class of eczematous dermatitis. Psoriasis, for example, affects about three percent of the world's population. See, Baker, Burton, Zieve, Principles of Ambulatory Medicine, Williams and Wilkins (1982).
The psoriatic syndromes are related by a constellation of symptoms including pruritis, pain, visible lesions, inflammation, hair and nail changes and, in up to 32% of the cases, debilitating arthritis. The skin lesions can be distributed as single lesions or lesions localized to one area, or may be regional and generalized in a universal pattern affecting the integument as well as the skin appendages (hair and nails). The presentation is rarely symmetrical and favors areas of friction.
The pathophysiology of the syndromes includes a marked decrease in epidermal turnover time resulting in a markedly increased number of mitotic cells in the dividing pool. This creates a vastly increased epidermal proliferation. The epidermis and the dermis appear to respond as an integrated unit and show primary changes in the keratinocytes and keratogenous zones of the epidermis and inflammatory changes in the dermis. The resulting lesions are located in an area of erythroderma and include papules and plaques with marked silvery-white scaling. The papules may become pustules upon contamination. See, Fitzpatrick, et al. Color Atlas and Synopsis of Clinical Dermatology McGraw Hill Book Co. (1983); Barker, Burton Zieve, Principles of Ambulatory Medicine, Williams & Wilkins, (1982).
Treatment for sufferers of psoriatic syndromes has been difficult. Treatment decisions are made considering the type of psoriasis, the stage of the disease, the site of involvement, the age of the patient and the degree of disability or disfigurement. It is well known that many treatments available must be curtailed or even removed from consideration depending on the factors mentioned above. For example, methotrexate, a highly toxic anti-metabolite and cytotoxic medicine, which is used in recalcitrant psoriasis, can be fatal to patients. Other methods of treatment are time consuming, expensive, show poor patient compliance and are poorly tolerated by many patients. These include, but are not limited to, Psorelen Long Wave Ultra Violet Light, Retinoid therapy, Tar, and intralesional injections of steroids (which are quite painful). In cases with secondary fungal infection, ketoconazole (Nizoral®), a very common and popular antifungal, is used. Ketoconazole, however, has serious side effects which may be fatal when combined with terfenadine; known by the public as Seldane® (a commonly used allergy medication).
Avoidance of these complications presents a welcome invitation to a new preparation that is well tolerated by a number of people suffering from psoriasis. As will be described below, α-MSH and/or its derivatives show efficacy in these areas.
Another area of dermatological abnormalities that show a positive response to α-MSH and/or its derivatives are the delayed hypersensitivity reactions, i.e. allergic contact dermatitis (an example would be a reaction from an exposure to poison ivy) and primary irritant contact dermatitis (an example would be a reaction from repeated exposure to certain substances to which a person may be hypersensitive).
Similar to psoriasis, and most of the dermatological disorders, contact dermatitis shows a constellation of integumentary changes. Among these are irregular and poorly outlined patches of erythema and edema, vesicles, erosions exuding serum, and crusts. In chronic forms of contact dermatitis, a person may suffer patches of lichenification (thickening of the epidermis with deepening of the skin lines in parallel or rhomboidal pattern), hyperpigmentation and scaring from excoriation.
Early and tolerated treatment is of a great benefit to people suffering from contact dermatitis. Unfortunately, the stan dby treatment is, again, antihistamines and steroids; oral and topical, i.e. oral in the acute phase and topical in the subacute and chronic phase. Although the steroids function well in reduction of symptoms, they share the same drawbacks as listed above. Additionally, steroids would not be used in a prophylactic way due to their list of adverse side effects. A medication is needed that survives both as a symptomatic treatment as well as a preventative one. This medication would have applications in many of the diseases listed as well as others with just as complicated nomenclature and pathophysiology.
Regardless of the difficult nomenclature, however, many diseases of the integumentary system share the same pathophysiology and, therefore, share similar symptoms and sequelae. Of these symptoms, inflammation, algisia and pruritis are the most common, and it is these symptoms to which physicians direct their attention in the empirical treatment of skin disease. As with the diseases mentioned above, the overwhelming first line of treatment for physicians treating skin disease, especially non-specialists in the area, is some preparation of a steroid-based medicine. Hydrocortisone, betamethasone and prednisolone are commonly used steroids in many prescription and over-the-counter preparations of anti-inflammatory and anti-pruritic topical preparations. Often a physician will use an antihistamine in addition to, or as an alternative for, steroid therapy to control the effects of vascular permeability that is the result of the release of histamine from mast cells in the primary stages of inflammation. See, Ryan and Majano, Inflammation, a Scope Publication, The Upjohn Company, (1977).
Although the use of topical steroids and antihistamines are useful, they carry with them a long history of well-established and unwanted side effects. For example, antihistamines cause drowsiness and can be poorly tolerated in many individuals. Topical steroids are known to create problems for the integument that may be worse than the lesion they were intended to ameliorate. Here, the treatment may be worse than the disease.
For example, topical steroid use for as little as two weeks can cause: 1) telangiectasia (dilation of capillaries and sometimes of terminal arteries producing an angioma of macular appearance, or hyperemic spot) which, can be quite unsightly; 2) skin atrophy or thinning of the skin; and 3), mask an infection or suppress the host response to invasion by opportunistic pathogens.
This latter point is of great importance in any dermatological disorder that may result in an open lesion. Open lesions are a notoriously favorable environment for opportunistic infection. The warmth, blood supply, pH, and necrotic tissue are all conducive to bacterial or fungal colonization. Using a steroid in this environment may slow the response to an infection and thereby mask commonly observed and treated signs and symptoms of an infection; namely, purulence or puss. Thus, a simple infection in the presence of a topical steroid can be masked to the point of serious infection or even sepsis.
Reduced killing of pathogens is a detrimental consequence of therapy with anti-infammatory drugs. In addition to α MSH's and/or its derivatives potent anti-inflammatory effects, a MSH and/or its derivatives shows anti-microbial efficacy as well. It has been shown that the influences of αMSH and/or its derivatives on common skin pathogens, i.e. Staphylococcus Aureus and Candida Albicans, showed bactericidal and fungicidal properties. See, Cutull, Cristiani, Lipton and Catania, Antimicrobial Effects of α MSH Peptides, Journal of Leukocyte Biology, Volume 67, February 2000.
It follows that the use of a preparation that could offer all the benefits of steroid preparations, antipyretics, analgesics, and antihistamines but without the attendant side effects, will be a great addition to the available avenues of treatment of these types of symptoms and these types of disorders.